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Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling

Oncogene volume 35, pages 2675–2680 (2016)Cite this article

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Abstract

It is well known that specific signal transduction inhibitors rarely suffice as anti-cancer agents. In most cases, tumors possess primary drug resistance due to their inherent heterogeneity, or acquire drug resistance due to genomic instability and acquisition of mutations. Here we expand our previous study of the novel compound, NT157, and show that it acts as a dual-targeting agent that invokes the blockage of two signal transduction pathways that are central to the development and maintenance of multiple human cancers. We show that NT157 targets not only IGF1R-IRS1/2, as previously reported, but also the Stat3 signaling pathway and demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice.

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Acknowledgements

We thank Professor Martin Myers (UMMS) for the Jak2 expression plasmids and Professor Scott Weed (WVU) for the GFP-Src expression plasmids. We thank Professor Ruth Halaban (Yale University) and Yale SPORE in Skin Cancer for providing us with the patient-derived melanoma cells (YUMAC and YUSIK), and Dr Michal Lotem (Hadassah Hospital) for providing us the patient-derived melanoma cells (M571 and M2068). We acknowledge Dr Salim Joubran from our laboratory who was instrumental in the chemistry of NT157. This study was supported by an ERC Advanced Grant (No. 249898) to AL by the NIH Skin Cancer SPORE p50 (No. CA093459), by four grants from the Office of the Chief Scientist in the Ministry of Industry, Trade and Labor of Israel to NovoTyr (HR, 2005–2012) and by Algen Biopharmaceuticals Ltd.

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Author notes

  1. H Reuveni

    Present address: 5Current address: TyrNovo Ltd, Herzliya, Israel.,

  2. H Reuveni and A Levitzki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Chemistry, Unit of Cellular Signaling, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    E Flashner-Abramson, S Klein, G Mullin, A Shir, Y Langut, H Reuveni & A Levitzki

  2. Department of Cancer Biology, Unit 173 UT, MD Anderson Cancer Center, Houston, TX, USA

    E Shoshan, R Song & M Bar-Eli

  3. NovoTyr Ltd., Tel Hai, Israel

    H Reuveni

Authors
  1. E Flashner-Abramson
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  2. S Klein
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  3. G Mullin
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  4. E Shoshan
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  5. R Song
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  6. A Shir
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  7. Y Langut
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  8. M Bar-Eli
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  9. H Reuveni
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  10. A Levitzki
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Corresponding authors

Correspondence to H Reuveni or A Levitzki.

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Supplementary Information accompanies this paper on the Oncogene website

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Flashner-Abramson, E., Klein, S., Mullin, G. et al. Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling. Oncogene 35, 2675–2680 (2016). https://doi.org/10.1038/onc.2015.229

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  • DOI: https://doi.org/10.1038/onc.2015.229

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